-
Clinica Chimica Acta; International... Mar 2020Activated protein C (APC) acts as an "on demand" anticoagulant, reducing thrombin formation. Reduced plasma levels of APC or protein C (PC) are associated with an... (Review)
Review
Activated protein C (APC) acts as an "on demand" anticoagulant, reducing thrombin formation. Reduced plasma levels of APC or protein C (PC) are associated with an increased risk of venous thromboembolism. APC also displays cytoprotective functions and its therapeutic use has been evaluated in severe sepsis and is under evaluation in several diseases with an important inflammatory component. In addition, different studies have revealed a potential role of PC/APC in disorders such as obesity, pneumonia, disseminated intravascular coagulation, Alzheimer, stroke, etc. Accordingly, the therapeutic value of different recombinant APC molecules that lack anticoagulant activity but retain the cytoprotective function is being tested in clinical trials for some of these diseases. Therefore, an available method to measure circulating APC in plasma is of great interests. About 16 different methods for the quantification of APC have been reported. Here, we will review the available assays, highlighting their advantages and disadvantages as well as their different stages of implementation and the most appropriate use for each method, including their potential clinical usefulness.
Topics: Humans; Protein C
PubMed: 31730817
DOI: 10.1016/j.cca.2019.11.005 -
Journal of Thrombosis and Haemostasis :... Jul 2007Protein C is a vitamin K-dependent plasma protein zymogen whose genetic mild or severe deficiencies are linked with risk for venous thrombosis or neonatal purpura... (Review)
Review
Protein C is a vitamin K-dependent plasma protein zymogen whose genetic mild or severe deficiencies are linked with risk for venous thrombosis or neonatal purpura fulminans, respectively. Studies over past decades showed that activated protein C (APC) inactivates factors (F) Va and VIIIa to down-regulate thrombin generation. More recent basic and preclinical research on APC has characterized the direct cytoprotective effects of APC that involve gene expression profile alterations, anti-inflammatory and anti-apoptotic activities and endothelial barrier stabilization. These actions generally require endothelial cell protein C receptor (EPCR) and protease activated receptor-1. Because of these direct cytoprotective actions, APC reduces mortality in murine endotoxemia and severe sepsis models and provides neuroprotective benefits in murine ischemic stroke models. Furthermore, APC reduces mortality in patients with severe sepsis (PROWESS clinical trial). Although much remains to be clarified about mechanisms for APC's direct effects on various cell types, it is clear that APC's molecular features that determine its antithrombotic action are partially distinct from those providing cytoprotective actions because we have engineered recombinant APC variants with selective reduction or retention of either anticoagulant or cytoprotective activities. Such APC variants can provide relatively enhanced levels of either cytoprotective or anticoagulant activities for various therapeutic applications. We speculate that APC variants with reduced anticoagulant action but normal cytoprotective actions hold the promise of reducing bleeding risk because of attenuated anticoagulant activity while reducing mortality based on direct cytoprotective effects on cells.
Topics: Anticoagulants; Humans; Models, Molecular; Protein C
PubMed: 17635713
DOI: 10.1111/j.1538-7836.2007.02491.x -
Current Opinion in Hematology Jan 2019The serine protease activated protein C (aPC) was initially characterized as an endogenous anticoagulant, but in addition conveys anti-inflammatory, barrier-protective,... (Review)
Review
PURPOSE OF REVIEW
The serine protease activated protein C (aPC) was initially characterized as an endogenous anticoagulant, but in addition conveys anti-inflammatory, barrier-protective, and pro cell-survival functions. Its endogenous anticoagulant function hampered the successful and continuous implantation of aPC as a therapeutic agent in septic patients. However, it became increasingly apparent that aPC controls cellular function largely independent of its anticoagulant effects through cell-specific and context-specific receptor complexes and intracellular signaling pathways. The purpose of this review is to outline the mechanisms of aPC-dependent cell signaling and its intracellular molecular targets.
RECENT FINDINGS
With the advent of new therapeutic agents either modulating directly and specifically the activity of coagulation proteases or interfering with protease-activated receptor signaling a better understanding not only of the receptor mechanisms but also of the intracellular signaling mechanisms controlled by aPC in a disease-specific and context-specific fashion, is required to tailor new therapeutic approaches based on aPC's anti-inflammatory, barrier-protective, and pro cell-survival functions.
SUMMARY
This review summarizes recent insights into the intracellular signaling pathways controlled by aPC in a cell-specific and context-specific fashion. We focus on aPC-mediated barrier protection, inhibition of inflammation, and cytoprotecting within this review.
Topics: Animals; Anticoagulants; Humans; Protein C; Sepsis; Signal Transduction
PubMed: 30451721
DOI: 10.1097/MOH.0000000000000473 -
International Journal of Molecular... Feb 2019Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions,... (Review)
Review
Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. Such beneficial effects have made APC an attractive target of research in a plethora of physiological and pathophysiological processes. Of note, the past decade or so has seen the emergence of its roles in cutaneous wound healing-a complex process involving inflammation, proliferation and remodelling. This review will highlight APC's functions and mechanisms, and detail its pre-clinical and clinical studies on cutaneous wound healing.
Topics: Animals; Biomarkers; Clinical Trials as Topic; Disease Models, Animal; Genetic Engineering; Humans; Protein C; Recombinant Proteins; Signal Transduction; Skin; Skin Ulcer; Translational Research, Biomedical; Wound Healing
PubMed: 30791425
DOI: 10.3390/ijms20040903 -
Protein and Peptide Letters 2018Protein C is a vitamin K dependent plasma zymogen. It inhibits clotting by inhibiting clotting by inactivating factor V and factor VIII. Protein C activation pathway... (Review)
Review
BACKGROUND
Protein C is a vitamin K dependent plasma zymogen. It inhibits clotting by inhibiting clotting by inactivating factor V and factor VIII. Protein C activation pathway involves three steps: (i) Activation of protein C; (ii) Inhibition of coagulation through inactivating factor V and VIII by activated protein C and (iii) Inhibition of activated protein C by plasma protease inhibitors specific for this enzyme. Proteinases converting the zymogen protein C (PC) of vertebrates into activated PC have been detected in several snake venoms. Most PC activators have been purified from venom of snake species belonging to the genera of the Agkistrodon complex. Unlike the physiological thrombin-catalyzed PC activation reaction which requires thrombomodulin as a cofactor, most snake venom activators directly convert the zymogen PC into the catalytically active form which can easily be determined by means of coagulation or chromogenic substrate techniques.
CONCLUSION
The fast-acting PC activator Protac® from Agkistrodon contortrix contortrix (Southern copperhead snake) venom has found a broad application in diagnostic practice for the determination of disorders in the PC pathway. Recently, screening assays for the PC pathway have been introduced, based on the observation that the PC pathway is probably the most important physiological barrier against thrombosis.
Topics: Coagulation Protein Disorders; Humans; Intercellular Signaling Peptides and Proteins; Peptides; Protein C; Snake Venoms
PubMed: 29921197
DOI: 10.2174/0929866525666180619101218 -
International Journal of Hematology Apr 2012Plasma protein C is a serine protease zymogen that is transformed into the active, trypsin-like protease, activated protein C (APC), which can exert multiple activities.... (Review)
Review
Plasma protein C is a serine protease zymogen that is transformed into the active, trypsin-like protease, activated protein C (APC), which can exert multiple activities. For its anticoagulant action, APC causes inactivation of the procoagulant cofactors, factors Va and VIIIa, by limited proteolysis, and APC's anticoagulant activity is promoted by protein S, various lipids, high-density lipoprotein, and factor V. Hereditary heterozygous deficiency of protein C or protein S is linked to moderately increased risk for venous thrombosis, while a severe or total deficiency of either protein is linked to neonatal purpura fulminans. In recent years, the beneficial direct effects of APC on cells which are mediated by several specific receptors have become the focus of much attention. APC-induced signaling can promote multiple cytoprotective actions which can minimize injuries in various preclinical animal injury models. Remarkably, pharmacologic therapy using APC demonstrates substantial neuroprotective effects in various murine injury models, including ischemic stroke. This review summarizes the molecules that are central to the protein C pathways, the relationship of pathway deficiencies to venous thrombosis risk, and mechanisms for the beneficial effects of APC.
Topics: Animals; Anticoagulants; Cytoprotection; Enzyme Activation; Humans; Models, Molecular; Mutation; Protein C; Protein S; Receptors, Cell Surface; Signal Transduction; Thrombomodulin; Venous Thrombosis
PubMed: 22477541
DOI: 10.1007/s12185-012-1059-0 -
Chest Sep 2003The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell... (Review)
Review
The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.
Topics: Blood Coagulation Factors; Humans; Protein C; Protein Conformation; Receptors, Cell Surface
PubMed: 12970121
DOI: 10.1378/chest.124.3_suppl.26s -
Methods in Molecular Biology (Clifton,... 2013Protein C (PC) is a 62-kDa vitamin K-dependent plasma zymogen which, after activation to serine protease, plays an important role in the physiologic regulation of blood...
Protein C (PC) is a 62-kDa vitamin K-dependent plasma zymogen which, after activation to serine protease, plays an important role in the physiologic regulation of blood coagulation. Given that PC is one of the major naturally occurring inhibitors of coagulation, acquired or hereditary deficiencies of this protein result in excessive thrombin generation. As a vast array of mutations are responsible for hereditary PC deficiencies, screening for their presence by DNA testing would require sequencing each entire gene involving numerous exons. Moreover, the knowledge of the gene mutation does not offer any benefit in the treatment of thrombophilic families, so the routine molecular characterization is not indicative. These defects are detected by functional or immunological assays. Measurement of PC activity is essential to identify subjects with both type I and type II PC defects. There is no need to routinely perform PC immunological assays. However, they are useful in order to distinguish type I from type II PC hereditary deficiency.
Topics: Blood Coagulation; Blood Coagulation Tests; Humans; Mutation; Protein C; Protein C Deficiency; Thrombophilia
PubMed: 23546729
DOI: 10.1007/978-1-62703-339-8_29 -
Seminars in Thrombosis and Hemostasis Aug 2003The protein C pathway comprises a major physiological anticoagulant system. Its major congenital defects, heterozygous deficiencies of protein C and protein S as well as... (Review)
Review
The protein C pathway comprises a major physiological anticoagulant system. Its major congenital defects, heterozygous deficiencies of protein C and protein S as well as activated protein C resistance due to G1691A mutated factor V (Factor V Leiden), are associated with pediatric venous thromboembolic disease. The protein C pathway is centrally involved in the control of both coagulation and inflammation during sepsis and other inflammatory conditions presenting with disseminated intravascular coagulation. This article reviews the physiology of the protein C pathway with special emphasis on pediatric aspects. Clinical implications of the protein C pathway defects in pediatric venous thromboembolism as well as acquired disturbances of protein C pathway during sepsis are discussed.
Topics: Blood Coagulation; Child; Female; Humans; Infant, Newborn; Inflammation; Pregnancy; Pregnancy Complications, Hematologic; Protein C; Protein C Deficiency; Sepsis; Venous Thrombosis
PubMed: 14517747
DOI: 10.1055/s-2003-42586 -
American Journal of Health-system... Jun 2009The role of protein C in critical illness is assessed. (Review)
Review
PURPOSE
The role of protein C in critical illness is assessed.
SUMMARY
Conversion of protein C to activated protein C (APC) requires thrombin and thrombomodulin. When thrombin is not bound to thrombomodulin, it can convert fibrinogen to fibrin, factor V to factor Va, and factor VIII to factor VIIIa but will not convert protein C to APC. When thrombin is bound to thrombomodulin, it can convert protein C to APC but cannot convert fibrinogen, factor V, or factor VIII. Activation of protein C is accelerated by the presence of endothelial protein C receptors. In conjunction with protein S, APC limits coagulation by inactivating factors Va and VIIIa, which decreases thrombin-mediated inflammation. By inhibiting the formation of thrombin and the release of proinflammatory cytokines, APC reduces the inflammatory response to infection. By inducing cell signaling, APC directly modulates the cellular response to infection, resulting in antiinflammatory, cytoprotective, and barrier-protective activities. APC is metabolized by protease inhibitors and other proteins in the plasma. Conversion of protein C to APC is impaired in severe sepsis. During severe sepsis, endogenous levels of the inactive precursor protein C are reduced because of decreased production by the liver and degradation by enzymes. More than 85% of patients with severe sepsis have low levels of protein C. Absolute levels of protein C correlate with morbidity and mortality outcomes of the sepsis population, regardless of age, infecting microorganism, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness.
CONCLUSION
The protein C pathway is a natural homeostatic regulator with multiple mechanisms of action. Blood protein C concentration is inversely correlated with morbidity and mortality in sepsis and other critical illness.
Topics: Anti-Infective Agents; Anticoagulants; Biomarkers; Clinical Trials as Topic; Critical Illness; Humans; Models, Biological; Polymorphism, Genetic; Protein C; Recombinant Proteins; Sepsis
PubMed: 19498123
DOI: 10.2146/ajhp080276